The long term goal of this project is to better understand the physiologic mechanisms of progesterone and a commonly-prescribed progestin on endothelial function and neural-vascular control in women. We will also explore potential interactions between the progestogens and estrogen on these physiologic mechanisms. Our aim is to investigate NO-dependent vasodilation in conduit and resistance vessels, to examine whether circulating levels of the vascular constrictor endothelin-1 is influenced by progestogens, and to investigate the effects of estrogen and progestogens on sympathetic outflow, baroreflex sensitivity, and vascular transduction. Our general approach is to suppress endogenous production of estrogen and progesterone using a gonadotropin-releasing hormone antagonist to create a hypoestrogen state. We will then administer progesterone or the progestin medroxyprogesterone acetate (MPA) alone or in combination with estrogen. The overall goal will be met by addressing the following specific aims: 1) Determine the acute effects of progesterone and MPA alone and in combination with estrogen on endothelium-dependent and endothelium-independent vasodilation in women. 2) Determine the acute effects of progesterone and MPA on sympathetic outflow, baroreflex sensitivity, and vascular transduction in women. 3) Determine the acute effects of progesterone and MPA on the contribution of nitric oxide and alpha-receptors to vasodilation and vasoconstriction in resistance vessels.PROJECT NARRATIVE Our current understanding of how natural and synthetic forms of progesterone impact the health of blood vessels and control of blood pressure in humans is lacking, despite the overwhelming use of these hormones in young and older women for contraceptive purposes, for hormone replacement therapy, and in the treatment of gynecological disorders. The goal of this project is to better understand how the natural and synthetic forms of progesterone impact blood vessel responsiveness and in the control of blood vessel tone by the sympathetic nervous system in women. We will also examine how these forms of progesterone interact with estrogen, with the goal to improve our understanding of the potential cardiovascular health benefits and risks of hormone therapy in both young and older women.